Although cancer therapies have advanced greatly over the years, significant challenges remain. Cancer therapies are generally associated with undesirable side effects, highlighting the need for therapies that are selective for tumor cells, and thus have decreased toxicity. In addition, chemotherapy- and radiation resistant cancers have a very high hurdle to successful therapy. In some instances, this resistance is due to the resistance of the cancerous cell to apoptosis.
For example, in prostate cancer, the resistance of prostate cancer cells to apoptosis plays a role in local and distant disease progression following conventional therapy (e.g. hormonal ablation and radiotherapy). The durable and local control rate (determined by serum levels of prostate specific antigen (PSA)) for patients with prostatic cancers of various stages and grades treated with primary radiation therapy alone is approximately 38%, and treatment of metastatic disease is palliative at best. The apoptotic machinery of most prostate cancer cells is intact, however, due to molecular alterations the cells are unable to execute the apoptotic pathways.
Selenium, a key component of a number of functional selenoproteins required for normal health, when in the inorganic selenite or an organic form such as selenomethione, has been shown to have both preventive and therapeutic effects. Inorganic and organic selenite can inhibit tumorigenesis in a variety of animal models at doses in excess of those required to support maximal activity of selenoproteins (Ip, et al., Current concepts of selenium and mammary tumorigenesis, In: Cellular and Molecular Biology of Breast Cancer, 479-494. Plenum Press, N.Y. (1997); Medina et al., Pathol Immunopathol Res, 7: 187-199 (1988); Milner et al., Fed Proc, 44: 2568-2572 (1985)). Epidemiology studies have shown a statistically significant inverse relationship between selenium levels and cancer risk (Combs et al., Selenium and cancer, In: Antioxidants and Disease Prevention, Ch. 8, 97-113. CRC Press, N.Y. (1997); Shamberger et al., CRC Crit Rev Clin Sci, 2: 211-219 (1971)). Human cancer prevention trials have shown that daily oral supplementation with of selenium-enriched yeast containing mostly L-selenomethionine (200 μg/day, approximately four times the recommended daily value) can significantly reduce the incidence of several major cancers including prostate, colon, and lung by nearly 50% (Clark et al., JAMA, 276: 1957-1963 (1996)).
While the majority of selenium research has focused on the use of long-term selenium intake for chemoprevention, little attention has been given to the cytotoxic effects of selenium and the potential use of selenium for chemotherapy in the clinical setting. The anti-tumor activities of selenium compounds are dependent upon the dose and chemical form. Selenite (oxidation state +4) undergoes thiol-dependent reduction to selenide (H2Se), which supplies selenium for the synthesis of selenoproteins, whereas selenomethionine is converted to selenocysteine before being degraded by the enzyme β-lyase to H2Se (Combs et al., Pharmacol. Ther., 79(3): 179-192 (1998)). Selenite metabolism results in the generation of superoxide and oxidative stress through its reductive reaction with reduced GSH (FIG. 1) (Combs, 1998). Selenate is metabolized to selenite in the body.
Selenite is capable of inhibiting cell growth and inducing apoptosis in a variety of human cancer cells lines in vitro (Menter et al., Cancer Epid Bio Prev, 9: 1171-1182 (2000); Zhong et al., Cancer Res, 61: 7071-7078 (2001)). Selenite (2 mg/kg, subcutaneous injection) has also been shown to inhibit the tumor growth of breast and ovarian cancer cell lines in vivo without apparent ill effects on the host (Watrach et al., Cancer Letters, 25: 41-47 (1984); Watrach et al., Cancer Letters, 15: 137-143 (1982); Caffrey et al., Cancer Letters, 121: 177-180 (1997)). The induction of apoptosis by Selenite is mediated by a redox mechanism involving induction of oxidative stress via superoxide formation and lowered intracellular GSH levels (Zhong, 2001). Mitochondria appear to serve as the main target for Selenite-induced apoptosis, with subsequent release of cytochrome c, followed by mitochondrial depolarization, caspase-3 activation and DNA fragmentation (Shen et al., Free Rad Biol Med, 30(1): 9-21 (2001). Several studies have also reported that selenium compounds selectively induce growth inhibition and apoptosis in cancer cells compared to normal cells (Menter, 2000; Fleming et al., Nut Cancer, 40(1): 42-49 (2001); Ghose et al., Cancer Res, 61: 7479-7487 (2001)). However, the molecular pathways underlying the differential response are poorly understood.
Thus, there remains a need in the field for methods of treating neoplastic disease, particularly drug- and radiation-resistant neoplasms, and particularly for improving the sensitivity of tumors to cancer therapy. The present invention addresses these needs.